Characterization of toxicity is fundamental to an assessment of human health risks resulting from exposure to chemicals. Basic to any characterization of chemical toxicity are studies of the fate and mechanisms of toxicity of chemicals of interest in one or more mammalian species. Such studies are designed to provide both applied knowledge of the fate of chemicals in the intact animal in support of toxicity tests conducted by the National Toxicology Program and basic knowledge of mechanisms of chemical toxicity. Each study is designed to address the impact of one or more factors such as dose, age, sex or route of exposure on the toxicity of the chemical(s) studied and the significance of this data to assessments of human health risks. Studies conducted during the current year have addressed the fate and mechanisms of toxicity of tris(2- chloroethyl)phosphate (TRCP), a flame retardant, used in many consumer products. TRCP was recently reported by the NTP to be a kidney carcinogen in rats. Approximately 50% of male rats exposed to 88 mg/kg for two years developed adenomas in renal tubules located in the outer margin of the medulla. Only 10% of female rats receiving the same dose developed adenomas in the same area. Studies currently underway are designed to determine the sex-related variations such as metabolism, clearance and concentration dependent toxicity which may account for the sex-dependent differences in carcinogenic responses observed in the bioassay. Results of these studies indicate that subtle differences in metabolism and dose in the target organ may account for the sex-dependent variations in carcinogenicity observed in the chronic studies. In another study, the combined toxicity of cimetidine, the active ingredient in the antiulcer drug Tagamet, and the pesticide diazinon is being investigated in an effort to determine if simultaneous exposure to these two compounds might enhance the toxicity of diazinon. Results of these studies indicate that diazinon is very rapidly metabolized and that simultaneous exposure to cimetidine has little effect on the half-life of diazinon, but does alter the ratio of some metabolites formed.